Actual and potential health and environmental effects of pesticides are of increasing concern, both to the public and regulatory agencies. Since their use in public health and agriculture is of critical importance it is essential to develop the background of fundamental knowledge necessary for their safe use and the development of even safer compounds. The theme of this program project is the elucidation of the mechanisms involved in the interaction of pesticides with living organisms, with particular emphasis on nontarget species, including humans. Mechanisms that may affect interactions between different pesticides and between pesticides and other xenobiotics are also emphasized, since multiple exposure is commonplace. The program consists of seven interrelated projects, statistical consultation and an administrative core. The first project involves dermal uptake, stressing the use of the isolated, perfused, porcine skin flap as an adjunct to human risk assessment models while the second concerns intra- and extra-cellular transport of proteins. Project three deals with oxidative mechanisms in pesticide metabolism and interactions while four deals with conjugation reactions and the use of invertebrates as non-mammalian models. Project five is concerned with the mechanism of action of glutathione S-transferase, with particular reference to the development of inhibitors. Projects six and seven deal with modes of toxic action, six with olfactory toxicants and seven with pesticides as tumor promoters. These projects are directed toward important aspects of pesticide toxicology and build on accomplishments of previous funding periods. We believe that such an integrated approach to pesticide toxicity will provide valuable insights into actual and potential effects of pesticides on human health and, further, will provide essential fundamental information to those concerned with the development of safer compounds.